This invention is in the general field of pharmacology, and relates in particular to formulations for drugs that benefit from a prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and from an enhanced opportunity of absorption in the stomach and upper GI tract rather than the lower portions of the GI tract. One goal in this invention is to release highly soluble drugs in a controlled manner over an extended period of time. Another goal is to extend the time of delivery into the stomach of drugs that are preferentially absorbed high in the GI tract, for purposes of achieving a greater and more prolonged therapeutic effect and thus reducing the frequency of administration required; a more efficient use of the drugs; and a more effective treatment of local stomach disorders. Another goal is to minimize both lower-tract inactivation of the drug and drug effects on the lower intestinal flora by confining the delivery and absorption of the drug to the upper GI tract.
Drugs that are administered in the form of conventional tablets or capsules become available to body fluids at a rate that is initially very high, followed by a rapid decline. For many drugs, this delivery pattern results in a transient overdose, followed by a long period of underdosing. This is a pattern of limited clinical usefulness. The delivery pattern was improved in the 1970""s with the introduction of a variety of controlled delivery systems. By providing relatively constant, controlled drug delivery, these systems avoided the overdose and the underdose effects. These improvements provided effective medication with reduced side effects, and achieved these results with reduced dosing frequency.
Many of these controlled delivery systems utilize hydrophilic, polymeric matrices that provide useful levels of control to the delivery of sparingly soluble drugs. For soluble drugs, however, and particularly for highly soluble drugs, such matrices do not provide adequate control over the drug release rate, instead resulting in a release that approximates first-order kinetics. That is, the rate of release is an inverse function of the square root of the elapsed time. With this pattern of release, most of the drug in the matrix is often released within the first hour in an aqueous medium.
One method of prolonging the release of a highly water-soluble drug is disclosed in International Patent Application Publication No. WO 96/26718, published Sep. 6, 1996 (applicant: Temple University; inventor: Kim). The method of this publication is the incorporation of the drug into a polymeric matrix to form a tablet that is administered orally. The polymer is water-swellable yet erodible in gastric fluids, and the polymer and the proportion of drug to polymer are chosen such that:
(i) the rate at which the polymer swells is equal to the rate at which the polymer erodes, so that the swelling of the polymer is continuously held in check by the erosion, and zero-order release kinetics (constant delivery rate) of the drug from the matrix are maintained;
(ii) the release of drug from the matrix is sustained over the full erosion period of the polymer, the tablet therefore reaching complete solution at the same time that the last of the drug is released; and
(iii) release of the drug from the matrix will be extended over a period of 24 hours.
A key disclosure in WO 96/26718 is that to achieve the release of drug in this manner requires the use of a low molecular weight polymer. If, by contrast, a high molecular weight polymer is used and the swelling rate substantially exceeds the erosion rate, the lack of erosion will prolong even further the delivery of the drug residing close to the center of the tablet and even prevent it from being released. Thus, there is no disclosure in WO 96/26718 that a drug of high water solubility can be released from a high molecular weight polymer in a period of time substantially less than 24 hours, or that any advantage can be obtained by the use of a polymer that does not erode as quickly as it swells. This failure is particularly significant since even swollen tablets will not remain in the stomach beyond the duration of the fed mode, which typically lasts for only 4 to 6 hours.
For drugs of any level of solubility, the retention of the drug in a tablet or other dosage form beyond the duration of the fed mode raises a number of problems that detract from the therapeutic efficacy of the drug. These problems arise from the tendency of the tablet when the patient is no longer in the fed mode to pass from the stomach into the small intestine, and over a period of 2-4 hours to pass through the small intestine, thus reaching the colon with the drug still in the tablet. This loss of effectiveness occurs with drugs that provide their maximum benefit with minimum side effects when absorbed in the stomach and upper GI tract rather than the colon. The reasons are either favorable conditions in the stomach, unfavorable conditions in the colon, or both.
For example, most orally administered antibiotics have a potential of altering the normal flora of the gastrointestinal tract, and particularly the flora of the colon. One result of these alterations is the overgrowth of the organism Clostridium difficile, which is a serious adverse event since this organism releases dangerous toxins. These toxins can cause pseudomembranous colitis, a condition that has been reported as a side effect of the use of many antibiotics. In its milder forms, pseudomembranous colitis can cause mild nausea and diarrhea while in its stronger forms, it can be life-threatening or fatal. Examples of highly soluble antibiotics that pose this type of threat are amoxicillin, cefuroxime axetil, and clindamycin. Cefuroxime axetil (i.e., the axetil ester of cefuroxime), for example, becomes active when hydrolyzed to free cefuroxime, but when this occurs prior to absorption, it can be detrimental to essential bacterial flora. Hydrolysis to the active form typically occurs in the tissues into which the ester has been absorbed, but if the ester reaches the lower intestine, enzymes in the lower intestine cause the hydrolysis to occur in the intestine itself, which not only renders the drug unabsorbable but also converts the drug to the active form where its activity alters the flora. Examples of sparingly soluble antibiotics that pose the same type of threat are clarithromycin, azithromycin, ceftazidine, ciprofloxacin, and cefaclor.
A goal of the present invention is to avoid this type of alteration of the lower intestinal flora by delivering antibiotics, regardless of their level of solubility, in a manner that confines their delivery to the stomach and upper small intestine. Slow, continuous delivery from a gastric retentive system assures that both drug delivery and drug absorption are confined to the upper GI tract. More efficient delivery of antibiotics will also avoid transient overdosing which is a major cause of overgrowth of Clostridium difficile. 
Another example is the class of drugs that are susceptible to degradation by exposure to gastric fluid, either by enzymes or low solution pH. The swellable hydrophilic matrix of the present invention protects the yet undelivered drug during the 4 to 6 hour delivery period during which the drug is continuously released while the dosage form is retained in the stomach. One example of such a drug is topiramate, a drug that is used for the treatment of epilepsy. Topiramate is absorbed preferentially high in the GI tract and is hydrolyzed by the acidic environment of the stomach. The dosage form and delivery system of the present invention will confine the delivery of the drug to the stomach and duodenum. As the drug diffuses out of the swollen matrix, it is susceptible to the acidic environment, but the undelivered drug is protected from degradation by the polymer matrix.
Another example is the class of drugs that are known to have an absorption window high in the GI tract, but are incompletely absorbed or have a wide absorption range, intrapatient as well as interpatient. One example of such a drug is cyclosporine, a drug of low solubility that is used as an immunosuppressant to reduce organ rejection in transplant surgery. In addition to this problem, cyclosporine is in general only incompletely absorbed (on the average around 30%), and the degree of absorption is highly variable from one patient to the next (ranging from about 5% to about 89%). The variability can be attributed in part to differences among the various disease states existing in the patients to whom the drug is administered, and differences in the length of time between the transplant surgery and the administration of the drug. The variability can also however be attributed to the poor aqueous solubility of the drug and to variations in the gastric emptying, variations in the length of time required for intestinal transit between the stomach and the colon, variations in mesenteric and hepatic blood flow, variations in lymph flow, variations in intestinal secretion and fluid volume, variations in bile secretion and flow, and variations in epithelial cell turnover. All of these variations are addressed by the dosage form and delivery system of the present invention, which by confining drug delivery to the stomach reduces these differences and maximizes the absorption of the cyclosporine.
Another example is the class of drugs that are susceptible to degradation by intestinal enzymes. The degradation occurs before the drug can be absorbed through the intestinal wall, leaving only a fraction of the administered dose available for the intended therapeutic action.
An example of a highly soluble drug that is susceptible to degradation by intestinal enzymes is the pro-drug doxifluridine (5xe2x80x2-deoxy-5-fluouridine (dFUR)). The activity of doxifluridine depends on its activation to 5-fluorouracil by pyrimidine nucleoside phosphorylases. These enzymes are found in tumors as well as in normal tissues, with their highest activity being in the small intestine. The activity of these enzymes in tumor cells is more than twice that of normal tissues. When doxifluridine is administered orally, it can be converted to 5-fluorouracil in the intestine before it reaches the tumors. 5-Fluorouracil is much more toxic than doxifluridine and causes intestinal toxicity (nausea and diarrhea) and severe damage to the intestinal villi. A goal of the present invention is to confine the absorption of doxifluridine to the stomach and upper GI tract, thereby avoiding or reducing its conversion to 5-fluorouracil and the attendant toxicity risk. A similar result is sought for other drugs with similar susceptibilities, such as cyclosporine and digoxin.
Another class of drugs whose effectiveness suffers when the drugs are not fully absorbed high in the GI tract are those that are susceptible to inactivation by drug transporters that reside in lower gastrointestinal tract enterocytes. The inactivation occurs before the drug penetrates the intestinal wall, here again leaving only a fraction of the administered dose available for the intended therapeutic action. One example of a drug transporter is the p-glycoprotein efflux system, in which a p-glycoprotein acts as an absorption barrier to certain drugs that are substrates for the p-glycoprotein. The barrier acts by attaching to these drugs and transporting them drug back into the lumen, e.g., the stomach, duodenum, jejunum/ileum or colon, from which they were absorbed, or preventing them from being absorbed at all. This restriction of the drug to the interior of the GI tract is effectively an inactivation of the drug if the drug must pass out of the GI tract into the bloodstream to be effective. The p-glycoprotein efflux system is useful in many respects, such as preventing toxic compounds from entering the brain. It interferes however in some cases with the efficacy of certain drugs that would otherwise be absorbed. The p-glycoprotein concentration is lowest in the stomach and increases in concentration down the GI tract to the colon where the p-glycoprotein is most prevalent. The dosage form of the present invention will release the drug over an extended period into the upper GI tract where p-glycoprotein is lowest.
Cyclosporine is an example of a drug of low solubility that is susceptible to inactivation by the p-glycoprotein efflux system, in addition to its susceptibility to degradation by colonic bacterial enzymes. Other examples of drugs of low solubility that are susceptible to the p-glycoprotein efflux system are the anti-cancer drug paclitaxel, ciprofloxacin, and the HIV protease inhibitors saquinavir, ritonavir, and nelfinavir. All of these drugs will benefit through preserved activity by the present invention.
A still further class of drugs that suffer in effectiveness when not fully absorbed before reaching the colon are drugs that require an acidic environment for effective bioavailability. For certain drugs, the pH at a given site within the GI tract is an essential determinant of the bioavailability of the drug, since the solubility of the drug varies with pH. The stomach has a low pH and hence an acidic environment, while the small intestine has a higher pH and hence an alkaline environment. Higher bioavailability is achieved in some cases by higher solubility, which with some drugs occurs in a more acidic environment, and in other cases by keeping the drugs in a non-ionized state that is necessary for absorption, which with some drugs also occurs in a more acidic environment. Acidic drugs that have a low pK, for example, are in the neutral form that is required for absorption and are therefore preferentially absorbed in the stomach. Examples of highly soluble drugs that achieve their highest bioavailability at a low pH are esters of ampicillin. Examples of low solubility drugs that behave similarly are iron salts, digoxin, ketoconazole, fluconazole, griseofulvin, itraconazole, and micoconazole. A further goal of the present invention is therefore to maximize the bioavailability of drugs of these types by confining them to the acidic environment of the stomach while controlling their release rate to achieve an extended release profile. The invention thus improves the efficiency of iron salts in the treatment of the various forms of anemia, the efficiency of digoxin in the treatment of the heart disease, and the efficiency of ketoconazole in the treatment of systemic fungal infections such as candidiasis, canduria, blastomycosis, coccidiomycosis, histoplasmosis, chronomycosis, and pacococcidiomycosis.
The invention also improves the efficiency of drugs that have at least one ionized group in the pH range of 5 through 8. Since this is the pH range encountered in the small intestine and the region of the colonic junction and ionized drugs are less absorbable than neutral drugs, this invention improves the absorption of these drugs by retaining them in the stomach environment. The invention also improves the efficiency of drugs that are degradable in an acidic environment such as that of the stomach by protecting them from the acidic environment until they are released from the dosage form, thereby reducing the duration of their exposure to the acidic environment.
A still further example of drugs that lose their efficacy upon reaching the lower portions of the GI tract are drugs that are soluble in an acidic environment but insoluble in an alkaline environment. The HIV protease inhibitor nelfinavir mesylate is one example of such a drug. Portions of the drug that are undissolved cannot be absorbed. Portions that are dissolved but not yet absorbed when they pass from the stomach into the small intestine may undergo precipitation and loss of their therapeutic benefit. This is confirmed by the fact that the presence of food in the GI tract substantially increases the extent of absorption of oral nelfinavir. Peak plasma concentration and area under the plasma concentration-time curve of nelfinavir are two-fold to three-fold greater when doses are administered with or following a meal. This is presumably due, at least in part, to enhanced retention of the drug in the stomach. A further goal of the present invention is therefore to provide a means of administering these drugs that will maximize their therapeutic effectiveness by extended, controlled release into the stomach.
It has now been discovered that drugs that are highly soluble in water can be administered orally in a manner that will prolong their delivery time to spread their release rate more evenly throughout the duration of the fed mode and beyond or not as desired. This significantly reduces, and often avoids, the problems of transient overdosing caused by the initial spike in concentration entering the blood stream immediately after administration and the subsequent underdosing, and instead controls the dosage to safer and more effective levels over an extended period of time.
It has further been discovered that for drugs of high, intermediate or low solubility, the problems arising from the release of the drugs in the lower GI tract, i.e., from the failure to absorb these drugs into the blood stream prior to reaching the lower GI tract, can be mitigated as well. For all drugs regardless of solubility, therefore, this invention corrects problems such as the overgrowth of detrimental intestinal flora by drugs that are toxic to normal intestinal flora, protection of undelivered acid-labile drugs in the dosage form, chemical degradation of drugs by intestinal enzymes, loss of bioavailability of the drugs due to their leaving the acidic environment of the stomach, and chemical degradation of the drugs due to the alkaline environment of the intestinal tract. By mitigating these problems, this invention thus further improves the efficiency of the use of these drugs.
Each of the beneficial effects enumerated above is achieved by using a formulation in which the drug is dispersed in a polymeric matrix that is water-swellable rather than merely hydrophilic, that has an erosion rate that is substantially slower than its swelling rate, and that releases the drug primarily by diffusion. It has further been found that the rate of diffusion of the drug out of the matrix can be slowed by increasing the drug particle size, by the choice of polymer used in the matrix, and/or by the choice of molecular weight of the polymer. The matrix is a relatively high molecular weight polymer that swells upon ingestion, preferably to a size that is at least about twice its unswelled volume, and that promotes gastric retention during the fed mode. Upon swelling, the matrix may also convert over a prolonged period of time from a glassy polymer to a polymer that is rubbery in consistency, or from a crystalline polymer to a rubbery one. The penetrating fluid then causes release of the drug in a gradual and prolonged manner by the process of solution diffusion, i.e., dissolution of the drug in the penetrating fluid and diffusion of the dissolved drug back out of the matrix. The matrix itself is solid prior to administration and, once administered, remains undissolved in (i.e., is not eroded by) the gastric fluid for a period of time sufficient to permit the majority of the drug to be released by the solution diffusion process during the fed mode. The rate-limiting factor in the release of the drug is therefore controlled diffusion of the drug from the matrix rather than erosion, dissolving or chemical decomposition of the matrix.
For highly soluble drugs, the swelling of the polymeric matrix thus achieves two objectivesxe2x80x94(i) the tablet swells to a size large enough to cause it to be retained in the stomach during the fed mode, and (ii) it retards the rate of diffusion of the highly soluble drug long enough to provide multi-hour, controlled delivery of the drug into the stomach. For drugs that are either sparingly soluble, of limited solubility, or of high solubility, and that experience any of the specific problems enumerated above upon reaching the lower GI tract prior to absorption into the bloodstream, the swelling of the polymeric matrix (i) renders the matrix sufficiently large to cause retention in the stomach during the fed mode, and (ii) localizes the release of the drug to the stomach and small intestine so that the drug will have its full effect without colonic degradation, inactivation, or loss of bioavailability.
In either of these aspects, the invention provides an effective means of using these drugs to treat local stomach disorders as well as a wide variety of disease conditions. For example, use of this invention provides more effective eradication of ulcer-causing bacteria in the gastric mucosa with soluble antibiotics. The invention also provides enhanced absorption of soluble drugs that are absorbed mostly in the stomach or high in the gastrointestinal tract, such as metformin hydrochloride or ciprofloxacin. The invention is also useful in providing a multi-hour flow of a drug past the upper part of the small intestine (the most efficient absorption site for many agents).
Details of these and other features of the invention will be apparent from the description that follows.